The present invention relates to novel compounds, compositions, and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates compositions and methods for preventing and treating an influenza infection, and processes for making such compounds, and synthetic intermediates employed in these processes.
Many disease-causing microorganisms possess a neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.
Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness. The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.
There are two major strains of influenza virus (designated A and B). Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.
Very recently the first influenza neuraminidase inhibitor, zanamivir, was approved. However, it can only be administered by inhalation. Therefore, there is a continuing need for improved agents for treatment and/or prevention of influenza infection. Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains. Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus. Compounds which are influenza neuraminidase inhibitors will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection.
The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:
L. Von Itzstein, et al., European Patent Application No. EP539204, published Apr. 28, 1993 (antiviral agent);
T. Honda, et al., European Patent Application No. EP823428, published Feb. 11, 1998 (sialidase inhibitor; influenza treatment);
T. Honda, et al., International Patent Application No. WO98/06712, published Feb. 19, 1998 (sialidase inhibitor; influenza remedy);
L. Von Itzstein, et al., International Patent Application No. WO95/20583, published Aug. 3, 1995 (viral neuraminidase inhibitor; influenza treatment);
P. Smith, International Patent Application No. WO95/18800, published Jul. 13, 1995 (viral neuraminidase inhibitor);
P. Colman, et al., International Patent Application No. WO92/06691, published Apr. 30, 1992 (viral neuraminidase inhibitor);
L. Von Itzstein, et al., U.S. Pat. No. 5,648,379, issued Jul. 15, 1997 (influenza treatment);
P. Reece, et al., International Patent Application No. WO97/32214, published Sep. 4, 1997 (bind to influenza virus neuraminidase active site); and
P. Reece, et al., International Patent Application No. WO98/21243, published May 23, 1998 (anti-influenza agent).
The following references disclose sialic acid derivatives with the disclosed utility listed after each reference:
Y. Ohira, et al., International Patent Application No.
WO98/11083, published Mar. 19, 1998 (antiviral agent);
Y. Ohira, European Patent Application No. EP882721, published Dec. 9, 1998 (antiviral agent); and
B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991) (Vibrio cholerae neuraminidase inhibitor).
The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:
Y. Babu, et al., U.S. Pat. No. 5,602,277, issued Feb. 11, 1997 (neuraminidase inhibitors);
M. Luo, et al., U.S. Pat. No. 5,453,533, issued Sep. 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);
Y. Babu, et al., International Patent Application No. WO96/30329, published Oct. 3, 1996 (neuraminidase inhibitor; viral infection treatment);
N. Bischofberger, et al., U.S. Pat. No. 5,763,483, issued Jun. 9, 1998 (neuraminidase inhibitor);
C. Kim, et al., International Patent Application No. WO99/31047, published Jun. 24, 1999 (neuraminidase inhibitor; influenza treatment);
V. Atigadda, et al., J. Med. Chem. 42 2332-2343 (1999) (influenza neuraminidase inhibitor); and
K. Kent, et al., International Patent Application No. 98/07685, published Feb. 26, 1998 (intermediates for the preparation of neuraminidase inhibitors).
C. Kim, et al., International Patent Application No. WO98/17647, published Apr. 30, 1998 discloses piperidine derivatives that are useful as neuraminidase inhibitors.
N. Bischofberger, et al., International Patent Application No. WO96/26933, published Sep. 6, 1996 and N. Bischofberger, et al., International Patent Application No. WO99/14185, published Mar. 25, 1999 disclose various substituted 6-membered ring compounds that are useful as neuraminidase inhibitors.
The following references disclose dihydropyran derivatives that are useful as viral neuraminidase inhibitors:
D. Andrews, et al., International Patent Application No. WO97/06157, published Feb. 20, 1997 and U.S. Pat. No. 5,919,819, issued Jul. 6, 1999; and
P. Cherry, et al., International Patent Application No. WO96/36628, published Nov. 21, 1996.
C. Kim, et al., U.S. Pat. No. 5,512,596, issued Apr. 30, 1996 discloses 6-membered aromatic ring derivatives that are useful as neuraminidase inhibitors.
G. Diana, et al., International Patent Application No.
WO98/03487, published Jan. 29, 1998 discloses substituted pyridazines that are useful for treatment of influenza.
B. Horenstein, et al., International Patent Application No.
WO99/06369, published Feb. 11, 1999 discloses piperazine derivatives that are useful as neuraminidase inhibitors.
The following references disclose substituted cyclopentanes that are useful as neuraminidase inhibitors and treatments for influenza:
Y. Babu, et al., International Patent Application No. WO97/47194, published Dec. 18, 1997; and
Y. Babu, et al., International Patent Application No. WO99/33781, published Jul. 8, 1999.
L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid that are useful as Vibrio cholerae sialidase inhibitors.
W. Brouillette, et al., International Patent Application No. WO99/14191, published Mar. 25, 1999, discloses substituted pyrrolidin-2-one compounds that are useful as neuraminidase inhibitors and treatments for influenza.
The following references disclose siastatin B analogs that are useful as neuraminidase inhibitors:
Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and
Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992).
C. Penn, UK Patent Application No. GB2292081, published Feb. 14, 1996 discloses the use of a neuraminidase inhibitor in combination with an influenza vaccine.
Thus, it would be an important contribution to the art to provide compounds which are neuraminidase inhibitors.
The present invention provides compounds of formula Ia and Ib 
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
R1 is selected from the group consisting of
(a) xe2x80x94CO2H,
(b) xe2x80x94SO3H,
(e) xe2x80x94SO2H,
(f) xe2x80x94PO3H2,
(g) xe2x80x94PO2H,
(h) tetrazolyl,
(i) xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94S(O)2xe2x80x94R11, and
(j) xe2x80x94SO2N(Txe2x80x94R11)R12;
wherein
T is selected from the group consisting of
(i) a bond, (ii) xe2x80x94C(xe2x95x90O)xe2x80x94, (iii) xe2x80x94C(xe2x95x90O)Oxe2x80x94, (iv) xe2x80x94C(xe2x95x90O)Sxe2x80x94, (v) xe2x80x94C(xe2x95x90O)NR36xe2x80x94, (vi) xe2x80x94C(xe2x95x90S)Oxe2x80x94, (vii) xe2x80x94C(xe2x95x90S)Sxe2x80x94, and (viii) xe2x80x94C(xe2x95x90S)NR36xe2x80x94;
R11 is selected from the group consisting of
(i) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv) (cycloalkyl)alkyl, (v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (viii) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl, (xii) heterocyclic, (xiii) (heterocyclic)alkyl, and (xiv) (heterocyclic)alkenyl; and
R12 and R36 are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (ix) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl, and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of
(a) xe2x80x94C(xe2x95x90O)xe2x80x94N(R*)xe2x80x94, (b) xe2x80x94N(R*)xe2x80x94C(xe2x95x90O)xe2x80x94, (b) xe2x80x94C(xe2x95x90S)xe2x80x94N(R*)xe2x80x94, (d) xe2x80x94N(R*)xe2x80x94C(xe2x95x90S)xe2x80x94, (e) xe2x80x94N(R*)SO2xe2x80x94, and (f) xe2x80x94SO2xe2x80x94N(R*)xe2x80x94, wherein R* is hydrogen, C1-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C5-C6 cycloalkenyl, (f) halo C1-C6 alkyl and (g) halo C2-C6 alkenyl;
or R2xe2x80x94Xxe2x80x94 is 
xe2x80x83wherein Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94and Y2 is xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(Raa)(Rbb)xe2x80x94 wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R2a is selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) halo C1-C6 alkyl, and (e) halo C2-C6 alkenyl;
R14 and R15 are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thiol-substituted alkyl, (vi) R37cO-substituted alkyl, (vii) R37cS-substituted alkyl, (viii) aminoalkyl, (ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-substituted alkyl, (xi) R37aOxe2x80x94(Oxe2x95x90)C-substituted alkyl, (xii) R37aSxe2x80x94(Oxe2x95x90)C-substituted alkyl, (xiii) R37aOxe2x80x94(Sxe2x95x90)C-substituted alkyl, (xiv) R37aSxe2x80x94(Sxe2x95x90)C-substituted alkyl, (xv) (R37aO)2xe2x80x94P(xe2x95x90O)-substituted alkyl, (xvi) cyanoalkyl, (xvii) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl, (xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl, (xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl)alkyl, (xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)-alkynyl, (xxviii) aryl, (xxxix)(aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl, (xxxiv) (heterocyclic)alkenyl, (xxxv) (heterocyclic)alkynyl, (xxxvi) xe2x80x94O-alkyl, (xxxvii) xe2x80x94NHalkyl, (xxxviii) xe2x80x94NH2, (xxxix) xe2x80x94N(alkyl)2, (xxxx) xe2x80x94OH, (xxxxi) xe2x80x94NHacyl, (xxxxii) xe2x80x94Nalkylacyl, (xxxxiii) xe2x80x94NHcarbamoyl, (xxxxiv) xe2x80x94Nalkylcarbamoyl, (xxxxv) xe2x80x94NHcarbamidyl, and (xxxxvi) xe2x80x94Nalkylcarbamidyl;
R37a is selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iii) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) C2-C12 alkynyl, (x) cycloalkyl, (x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl, (xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)alkenyl, (xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl, (xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and (xxiv) (heterocyclic)alkynyl;
R37c at each occurrence is independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)-alkenyl, (x) (cycloalkyl)alkynyl, (xii) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl, (xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic, (xx) (heterocyclic)alkyl, (xxi) (heterocyclic)-alkenyl, (xxii) (heterocyclic)alkynyl, (xxiii) xe2x80x94C(xe2x95x90O)xe2x80x94R14, (xxiii) xe2x80x94C(xe2x95x90S)xe2x80x94R14, (xxv) xe2x80x94S(O)2xe2x80x94R14 and (xxvi) hydroxyalkyl;
Y is selected from the group consisting of
(a) C2-C5 alkenyl,
(b) C2-C5 haloalkenyl,
(c) C2-C5 alkynyl,
(d) C5 cycloalkenyl,
(e) C5 cycloalkenyl-C1-to-C3-alkyl,
(f) C5 cycloalkenyl-C2-to-C3-alkenyl,
(g) phenyl,
(h) halo-substituted phenyl,
(i) xe2x80x94(CHR39)nC(xe2x95x90Q2)R22, and
(j) a heterocyclic ring having from 3 to 6 ring atoms;
with the proviso that Y is not 
wherein n is 0, 1, or 2; and Q2 is O, S, NR25, or CHR26;
R22 is selected from the group consisting of
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) xe2x80x94N(R28a)(R28b), (xxiii) xe2x80x94CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) xe2x80x94NHNH2, (xxviii) xe2x80x94N(CH3)NH2, or (xxix) xe2x80x94NHNH(CH3);
R25 is hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94CN, or xe2x80x94NO2;
R26 is hydrogen, methyl or ethyl;
R28a is hydrogen, hydroxy, methyl, ethyl, amino, xe2x80x94NHCH3, xe2x80x94N(CH3)2, methoxy, ethoxy, or xe2x80x94CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
with the proviso that when Q2 is CHR26 then R22 is selected from the group consisting of hydrogen, xe2x80x94CH3, xe2x80x94C2H5, xe2x80x94C3H7, xe2x80x94OCH3, xe2x80x94SCH3, xe2x80x94Oxe2x80x94C2H5, and xe2x80x94Sxe2x80x94C2H5;
R6 is independently selected from the group consisting of
(a) hydrogen, (b) C1-C12 alkyl, (c) C2-C12 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cyclo alkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl, (i) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (l) (aryl)alkenyl, (m) heterocyclic, (m) (heterocyclic)alkyl, and (o) (heterocyclic)alkenyl; and
R8 and R9 are independently selected from the group consisting of
(a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, (f) fluorine, and (g) xe2x80x94NH2,
xe2x80x83with the proviso that the total number of atoms, other than hydrogen, in each of R8 and R9, is 6 atoms or less; and
R10 is selected from the group consisting of
(a) hydrogen,
(b) C1-C6 alkyl,
(c) xe2x80x94NH2, and
(d) xe2x80x94OH
xe2x80x83with the proviso that the total number of atoms, other than hydrogen, in each of R10, is 6 atoms or less.
Further provided are compounds of formulas Iaxe2x80x2 and Ibxe2x80x2
wherein the substituents are as defined hereinabove.
Still further provided are compounds of formula Iaxe2x80x3 and Ibxe2x80x3
wherein all substituents are as defined hereinabove.
Still further provided are intermediates and processes for preparing compounds of formula Ia and Ib.
Additionally provided are methods of using compounds of formula I for the inhibition of a neuraminidase enzyme of disease-causing microorganisms; particularly viral neuraminidase, and, especially influenza neuraminidase.
Also provided are compounds of formula Ia and Ib that inhibit neuraminidase from both A and B strains of influenza.
Still further provided are methods for the prophylaxis and/or treatment of influenza infection in humans and other mammals using compounds of formula Ia and Ib.
Additionally provided are compounds that exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
Also provided are compounds that can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
The term xe2x80x9cacid protecting groupxe2x80x9d as used herein refers to groups used to protect acid groups (for example, xe2x80x94CO2H, xe2x80x94SO3H, xe2x80x94SO2H, xe2x80x94PO3H2, xe2x80x94PO2H groups and the like) against undesirable reactions during synthetic procedures. Commonly used acid protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley and Sons, New York (1991) which is incorporated herein by reference. Most frequently, such acid protecting groups are esters.
Such esters include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
arylalkyl esters including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
silylesters, especially, (tri-loweralkyl)silyl esters, (di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like; and the like.
Preferred acid protecting groups are loweralkyl esters.
The term xe2x80x9cactivated carboxylic acid groupxe2x80x9d as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,Nxe2x80x2-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
The term xe2x80x9cacylxe2x80x9d as used herein, refers to groups having the formula xe2x80x94C(xe2x95x90O)xe2x80x94R95 wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups as R95 are loweralkyl groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.
The term xe2x80x9cacylalkylxe2x80x9d as used herein refers to an acyl group appended to an alkyl radical. Representative examples of acylalkyl groups include acetylmethyl, acetylethyl, propionylmethyl, propionylethyl and the like.
The term xe2x80x9cacylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94NHR89 wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.
The term xe2x80x9cacyloxyalkylxe2x80x9d as used herein refers to an acyloxy group (i.e., R95xe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R95 is hydrogen or an alkyl group) which is appended to an alkyl radical. Representative examples of acyloxyalkyl include acetyloxymethyl, acetyloxyethyl, propioyloxymethyl, propionyloxyethyl and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term xe2x80x9clower alkenylxe2x80x9d refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
The term xe2x80x9calkenylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term xe2x80x9clower alkenylenexe2x80x9d refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94OR81 where R81 is an alkenyl group.
The term xe2x80x9calkoxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94OR99 wherein R99 is an alkyl group. Preferred R99 groups are loweralkyl groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tert-butoxy, and the like.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein, refers to groups having the formula xe2x80x94Oxe2x80x94R96xe2x80x94Oxe2x80x94R97 wherein R97 is loweralkyl, as defined herein, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein, refers to groups having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94R80, where R80 is an alkoxy group.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d as used herein, refers to groups having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94R79, appended to the parent molecular moiety through an alkylene linkage, where R79 is an alkoxy group.
The term xe2x80x9calkoxycarbonyloxyalkylxe2x80x9d as used herein refers to an alkoxycarbonyloxy group (i.e., R80xe2x80x94C(O)xe2x80x94O wherein R80 is an alkoxy group) appended to an alkyl radical. Representative examples of alkoxycarbonyloxyalkyl include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl and the like.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term xe2x80x9cloweralkylxe2x80x9d refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms. Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like. The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, xe2x80x94N(R27)xe2x80x94 and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term xe2x80x9calkylaminoxe2x80x9d as used herein, refers to groups having the formula xe2x80x94NHR91 wherein R91 is an alkyl group. Preferred R91 groups are loweralkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
The term xe2x80x9calkylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon. The term xe2x80x9clower alkylenexe2x80x9d refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include groups such as, for example, methylene (xe2x80x94CH2xe2x80x94), 1,2-ethylene (xe2x80x94CH2CH2xe2x80x94), 1,1-ethylene (xe2x80x94CH(CH3)xe2x80x94), 1,3-propylene (xe2x80x94CH2CH2CH2xe2x80x94), 2,2-dimethylpropylene (xe2x80x94CH2C(CH3)2CH2xe2x80x94), and the like. The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, xe2x80x94N(R27)xe2x80x94 and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94SO2xe2x80x94R78, where R78 is an alkyl group. Preferred groups R78 are loweralkyl groups.
The term xe2x80x9calkylsulfonylaminoxe2x80x9d as used herein refers to the group having the formula, xe2x80x94SO2xe2x80x94R77, appended to the parent molecular moiety through an amino linkage (xe2x80x94NHxe2x80x94), where R77 is an alkyl group. Preferred groups R77 are loweralkyl groups.
The term xe2x80x9calkynylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term xe2x80x9clower alkynylxe2x80x9d refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term xe2x80x9calkynylenexe2x80x9d as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term xe2x80x9clower alkynylenexe2x80x9d refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms. Representative examples of alkynylene groups include groups such as, for example, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94, and the like.
The term xe2x80x9caminoalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended an amino (xe2x80x94NH2) group.
The term xe2x80x9carylxe2x80x9d as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (xe2x95x90O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, NH2C(xe2x95x90O)xe2x80x94, cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted (heterocyclic)alkoxy, unsubstituted (heterocyclic)oxy and xe2x80x94SO3H. Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.
The term xe2x80x9c(aryl)alkenylxe2x80x9d refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl)alkenyl groups include groups such as, for example phenylethylenyl, phenylpropenyl, and the like.
The term xe2x80x9c(aryl)alkylxe2x80x9d refers to a loweralkyl group having appended thereto an aryl group. Representative examples of (aryl)alkyl groups include groups such as, for example benzyl and phenylethyl.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94Oxe2x80x94R76 where R76 is an arylalkyl group.
The term xe2x80x9c(aryl)alkynylxe2x80x9d refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl)alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94Oxe2x80x94R72, where R72 is an aryl group.
The term xe2x80x9ccarbamidylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2.
The term xe2x80x9ccarbamoylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94C(xe2x95x90O)xe2x80x94NH2.
The term xe2x80x9ccarboxyalkylxe2x80x9d as used herein, refers to the group having the formula, xe2x80x94R64xe2x80x94COOH, where R64 is a lower alkylene group.
The term xe2x80x9ccyanoalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended a cyano group (xe2x80x94CN).
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term xe2x80x9c(cycloalkenyl)alkenylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
The term xe2x80x9c(cycloalkenyl)alkylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.
The term xe2x80x9c(cycloalkenyl)alkynylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornene, bicyclo[2.2.2]octane and the like.
Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term xe2x80x9c(cycloalkyl)alkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term xe2x80x9c(cycloalkyl)alkenylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkenyl radical. Representative examples of (cycloalkyl)alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.
The term xe2x80x9c(cycloalkyl)alkynylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl)alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
The term xe2x80x9cdialkylaminoll as used herein, refers to groups having the formula xe2x80x94N(R90)2 wherein each R90 is independently a lower alkyl group. Representative examples of dialkylamino include dimethylamino, diethylamino, N-methyl-N-isopropylamino and the like.
The term xe2x80x9cdialkylaminoalkylxe2x80x9d as used herein refers to a dialkylamino group appended to an alkyl radical. Representative examples of dialkylaminoalkyl include dimethylaminomethyl, dimethylaminoethyl, N-methyl-N-ethylaminoethyl and the like.
The term xe2x80x9cdialkylaminocarbonylalkylxe2x80x9d as used herein refers to a xe2x80x94C(O)xe2x80x94N(R90)2 group (wherein each R90 is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonylalkyl include dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, N-methyl-N-ethylaminocarbonylethyl and the like.
The term xe2x80x9cdialkylaminocarbonyloxyalkylxe2x80x9d as used herein refers to a xe2x80x94Oxe2x80x94C(O)xe2x80x94N(R90)2 group (wherein each R90 is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonyloxyalkyl include dimethylaminocarbonyloxymethyl, diethylaminocarbonyloxymethyl, N-methyl-N-ethylaminocarbonyloxyethyl and the like.
The term xe2x80x9cenantiomerically enrichedxe2x80x9d as used herein refers to a compound which comprises unequal amounts of the enantiomers of an enantiomeric pair. In other words, an enantiomerically enriched compound comprises more than 50% of one enantiomer of an enantiomeric pair and less than 50% of the other enantiomer of the enantiomeric pair. Preferably, a compound that is enantiomerically enriched comprises predominantly one enantiomer of an enantiomeric pair. Preferably, an enantiomerically enriched compound comprises greater than 80% of one enantiomer of an enantiomeric pair and less than 20% of the other enantiomer of the enantiomeric pair. More preferably, an enantiomerically enriched compound comprises greater than 90% of one enantiomer of an enantiomeric pair and less than 10% of the other enantiomer of the enantiomeric pair. Even more preferably, an enantiomerically enriched compound comprises greater than 95% of one enantiomer of an enantiomeric pair and less than 5% of the other enantiomer of the enantiomeric pair. Even more highly preferably, an enantiomerically enriched compound comprises greater than 97% of one enantiomer of an enantiomeric pair and less than 3% of the other enantiomer of the enantiomeric pair. Yet even more highly preferably, an enantiomerically enriched compound comprises greater than 98% of one enantiomer of an enantiomeric pair and less than 2% of the other enantiomer of the enantiomeric pair. Most preferably, an enantiomerically enriched compound comprises greater than 99% of one enantiomer of an enantiomeric pair and less than 1% of the other enantiomer of the enantiomeric pair.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalidexe2x80x9d as used herein refers to F, Cl, Br or I.
The term xe2x80x9chaloalkenylxe2x80x9d as used herein refers to a loweralkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2-difluoroethylene, trifluoroethylene, 1,1,1-trifluoro-2-propylene and the like.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94OR69, where R69 is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
The term xe2x80x9chaloalkylxe2x80x9d as used herein, refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and the like.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl, , 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyl,1,3-dithiolinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula 
where X* is xe2x80x94CH2 or xe2x80x94Oxe2x80x94 and Y* is xe2x80x94C(O)xe2x80x94 or [xe2x80x94C(R92)2xe2x80x94]v where R92 is hydrogen or C1-C4 alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.
The term xe2x80x9c(heterocyclic)alkenylxe2x80x9d as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
The term xe2x80x9c(heterocyclic)alkoxyxe2x80x9d as used herein refers to the group having the formula, xe2x80x94OR68, where R68 is a (heterocyclic)alkyl group.
The term xe2x80x9c(heterocyclic)alkylxe2x80x9d as used herein refers to a heterocyclic group appended to a loweralkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
The term xe2x80x9c(heterocyclic)alkynylxe2x80x9d as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.
The term xe2x80x9c(heterocyclic)carbonylalkylxe2x80x9d as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyl group. Representative examples of (heterocyclic)carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
The term xe2x80x9c(heterocyclic)carbonyloxyalkylxe2x80x9d as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyloxy group (i.e., xe2x80x94C(O)xe2x80x94Oxe2x80x94). Representative examples of (heterocyclic)carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl and the like.
The term xe2x80x9c(heterocyclic)oxyxe2x80x9d as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (xe2x80x94Oxe2x80x94).
The term xe2x80x9chydroxy protecting group,xe2x80x9d hydroxyl protecting group,xe2x80x9dor xe2x80x9cxe2x80x94OH protecting group,xe2x80x9d as used herein, refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991) which is incorporated by reference herein. Such hydroxy protecting groups include:
methyl ether;
substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;
benzyl ether;
substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to the group having the formula, xe2x80x94R65 xe2x80x94OH, where R65 is an alkylene group
The term xe2x80x9cleaving groupxe2x80x9d as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, alpha-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl (phenyl-Sxe2x80x94), triphenylmethylsulfenyl (trityl-Sxe2x80x94) and the like; sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)xe2x80x94t-butylsulfinyl (t-Bu-S(O)xe2x80x94) and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, alpha, alpha-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like; p-methoxyphenyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to groups having the formula xe2x80x94SR98 wherein R98 is an alkyl group. Preferred groups R98 are lower alkyl groups.
The term xe2x80x9cthio-substituted alkylxe2x80x9d as used herein refers to an alkyl radical to which is appended a thiol group (xe2x80x94SH).
As used herein, the terms xe2x80x9cSxe2x80x9d and xe2x80x9cRxe2x80x9d configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By xe2x80x9csubstantially freexe2x80x9d is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.
Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.
Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.
Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
In addition, solvates and hydrates of the compounds of Formula Ia or Ib are meant to be included in this invention.
When any variable (for example R1, R2, R3, m, n, etc.) occurs more than one time in any substituent or in the compound of Formula Ia or Ib or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
This invention is intended to encompass compounds having Formula Ia or Ib when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
Compounds of the invention can be prepared according to the methods described in the Schemes as shown below. Throughout the Schemes, methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
Synthetic Methods
The compounds and processes of the invention will be better understood in connection with the following synthetic Schemes which illustrate methods by which the compounds of the invention can be prepared. The compounds of the invention can be prepared by a variety of procedures. Representative procedures are shown in Schemes 1-56.
It will be readily apparent that other compounds of the invention can by synthesized by the substitution of appropriate starting materials and reagents in the syntheses shown below. It will also be apparent that protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, to successfully complete the syntheses of compounds of the invention. Commonly used protecting groups are disclosed in Greene, (op. Cit).
The other compounds of the invention can be readily prepared from the compounds described herein using techniques known in the chemical literature. The methods required are known and can be readily practiced by those having ordinary skill in the art.
The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA); Alfa Aesar (Ward Hill, Mass. 01835-9953); Eastman Chemical Company (Rochester, N.Y. 14652-3512); Lancaster Synthesis Inc. (Windham, N.H. 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, N.J. 08901); Pfaltz and Bauer (Waterbury, Conn. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
Starting materials and reagents are available commercially or can be prepared synthetically by known methods such as those disclosed in Larock, xe2x80x9cComprehensive Organic Transformation. A Guide to Functional Group Preparations,xe2x80x9d VCH Publishers, New York (1989).
All of the reactions discussed in the Schemes are run in solvents in which the starting materials and products are not reactive, unless otherwise specified and those in which the starting materials are at least partially soluble. The appropriate solvent for each reaction will be apparent to one skilled in the art. For example, possible solvents, which can be used include THF, DCM, MeCN, DMF, EtOAc, hexanes, toluene, benzene, DMSO, MeOH, EtOH, i-PrOH, water, dioxane, anisole, pyridine, aniline, TEA, NMP, HMPA, glyme, diglyme, xylene, DME, acetone, cyclohexane, glycerol, 1,2-dichloroethane, tertiary-butyl methyl ether, ethyl ether, methyl ether, PhoPh, chloroform, carbon tetrachloride, dioxane, morpholine, 1,1,1-trichloroethane, trifluoroacetic acid, AcOH, hydrochloric acid, sulfuric acid, perchloric acid, nitric acid and mixtures thereof.
The term xe2x80x9chydroxy-protecting group,xe2x80x9d as used herein, refers to selectively removable groups which protect hydroxyl groups against undesirable reactions during synthetic procedures. The use of hydroxy-protecting groups is well-known in the art and is discussed in T. H. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd edition, John Wiley and Sons, New York (1991), pp 10-86. Examples of hydroxy-protecting groups include methylthiomethyl, tertiary-butyldimethylsilyl, tertiary-butyldiphenylsilyl, acetyl, benzoyl, and the like.
Numerous asymmetric centers exist in the compounds of the invention. The invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds of the invention can be made by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation as, for example, by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques, or by direct separation of the optical enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the art.
Abbreviations
Abbreviations used in the descriptions of the Schemes and the examples that follow are: THF for tetrahydrofuran; AcOH for acetic acid; Ac for acetate; MeCN for acetonitrile; MeOH for methanol; TMS for trimethylsilyl; TES for triethylsilyl; TFA for trifluoroacetic acid; TBDMS for tertiary-butyldimethylsilyl; TMSCl for trimethylsilyl chloride; TMSBr for trimethylsilyl bromide; TMSN3 for trimethylsilyl azide; BF3.OEt2 for boron trifluoride diethyl etherate; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; TEA for triethylamine; TMSOTf for trimethylsilyl triflate; DMF for N,N-dimethylformamide; Ph for phenyl; DCM for dichloromethane; DME for dimethoxyethane; DMSO for dimethyl sulfoxide; Et for ethyl; i-Pr for isopropyl; TBME for tertiary-butyl methyl ether; PBu3 for tributylphosphine, HMPA for hexamethylphosphoramide; Pb(OAc)4 for lead (IV)acetate; NMP for N-methylpyrrolidine; AIBN for 2,2xe2x80x2-azobisisobutyronitrile; MCPBA for meta-chloroperbenzoic acid; NMO for N-methylmorpholine N-oxide; TBAF for tetrabutylammonium fluoride; NaOMe for sodium methoxide; NaOEt for sodium ethoxide; TsOH for paratoluenesulfonic acid; PPh3 for triphenylphosphine; PEt3 for triethylphosphine; and P(OEt)3 for triethyl phosphite; nosyl for para-nitrophenylsulfonyl; DMAP for N,N-dimethylaminopyridine; acac for acetylacetonate, dba for dibenzylideneacetone; PSI for pounds per square inch; PhoPh for diphenylether; brosyl for para-bromophenylsulfonyl; PCC for pyridinium chlorochromate; dppf for 1,1xe2x80x2-bis(diphenylphosphino)ferrocene. 
As shown in Scheme 1, the conversion of (i) to (1A) can be accomplished by treating the former with a protecting group precursor, and an additive in a solvent. Specific examples of protecting group precursors include acetaldehyde, acetone, benzaldehyde, para-methoxybenzaldehyde, 3-pentanone, cyclohexanone, and 2,2-dimethoxypropane. Specific examples of additives include acids and bases. More preferred are the following acids: triflic acid, TFA, TsOH and hydrogen chloride. Since water is generated during the course of the reaction, the reaction can be dried by azeotropic removal of the water. An appropriate solvent for this conversion, therefore, is one which azeotropes with water. Specific examples of solvents which azeotrope with water include benzene, toluene, and xylene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a solution of (i), benzaldehyde, and TsOH in toluene is refluxed for about 10 hours. The water is removed azeotropically.
Conversion of (1A) to (1B) can be accomplished by treating the former with a free radical precursor and a free radical initiator in a solvent. Specific examples of free radical precursors include N-bromosuccinimide, N-chlorosuccinimide, Br2, and Cl2. Specific examples of free radical initiators include AIBN and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat. Specific examples of solvents include benzene, toluene, and xylene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1A) is treated with AIBN and N-bromosuccinimide in refluxing benzene for about four hours. 
As shown in Scheme 2, the conversion of (1B) to (1C) can be accomplished by treating the former with an organostannane and a free radical initiator in a solvent. Specific examples of organostannanes include 2-(tributylstannyl)furan, tributyltin hydride, allyltributyltin, vinyltributyltin, and 2-(tributylstannyl)thiophene. Specific examples of free radical initiators include AIBN and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat. Specific examples of solvents include benzene, toluene, and xylene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1B), allyltributyltin and AIBN in benzene are refluxed for about 10 hours.
The conversion of (1C) to (1D) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1C) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about two hours. 
As shown in Scheme 3, the conversion of (1D) to (1E) can be accomplished by treating the former with a base and an alcohol. Specific examples of bases include K2CO3, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, and isopropanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1D) in methanol at room temperature is treated with potassium carbonate for about 30 minutes.
The conversion of (1E) to (1F) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1E) in DCM at about 0xc2x0 C. is treated with benzoyl chloride and pyridine for about 5 hours. 
As shown in Scheme 4, the conversion of (1F) to (1G) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1F) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about 10 hours.
The conversion of (1G) to (1H) can be accomplished by treating the former with a base, and an alcohol. Specific examples of bases include K2CO3, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, and isopropanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1G) in methanol at room temperature is treated with potassium carbonate for about 30 minutes. 
As shown in Scheme 5, the conversion of (1H) to (1I) can be accomplished by treating the former with a base in a solvent. Specific examples of bases include potassium tertiary-butoxide, diisopropylethylamine, and DBU. Specific examples of solvents include THF, chloroform, TBME, and benzene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1H) in THF is treated with DBU and refluxed for about 6 hours.
The conversion of (1I) to (1J) can be accomplished by treating the former with a nucleophile and an additive. Specific examples of nucleophiles include NaN3, TMSN3, TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN3 and TMSN3. Specific examples of additives include acids and bases. More preferred are the following acids: NH4Cl, (NH4)2SO4, and AcOH. Specific examples of solvents include MeOH, EtOH, i-PrOH, NMP, water, and mixtures thereof. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (1I), NaN3 and NH4Cl in methanol-water is refluxed for about 5 hours. 
As shown in Scheme 6, the conversion of (1J) to (1K) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1J) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about two hours.
The conversion of (1K) to (1L) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include phosphines followed by water and base, and H2S and pyridine. More preferred are the following phosphines: PPh3 and PEt3. Specific examples of bases include TEA, NH4OH, and NaOH. Specific examples of solvents include THF, MeOH, TBME and DCM. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1K) in THF at room temperature is treated with PPh3 for about two hours, followed by water and TEA for about 10 hours. 
As shown in Scheme 7, the conversion of (1L) to (1M) can be accomplished by treating the former with a protecting group and a base in a solvent. Specific examples of protecting groups include trityl, nosyl and brosyl. Specific examples of base include pyridine, TEA and 2,6-lutidine. Specific examples of solvents include DCM, THF, chloroform and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1L) in DCM at about 0xc2x0 C. is treated with trityl chloride and TEA for about two hours.
The conversion of (1M) to (1N) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol. Specific examples of solvents include an aforementioned alcohol, THF, 1,1,1-trichloroethane, DCM and chloroform. Although the reaction generally proceeds at about 75xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1M) in isopropanol is treated with BF3.OEt2 and heated to about 75xc2x0 C. for about two hours.
The conversion of the intermediate compound to (1N) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1E) in pyridine at room temperature is treated with acetic anhydride and pyridine for about 12 hours. 
As shown in Scheme 8, the conversion of (1N) to (1O) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (1N) in THF at room temperature is treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 9, the conversion of (1M) to (2A) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol. Specific examples of solvents include an aforementioned alcohol, THF, 1,1,1-trichloroethane, DCM, and chloroform. Although the reaction generally proceeds at about 75xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1M) in 3-pentanol is treated with BF3.OEt2 and heated to about 75xc2x0 C. for about two hours.
The conversion of the intermediate compound to (2A) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1E) in pyridine at room temperature is treated with acetic anhydride and pyridine for about 10 hours.
The conversion of (2A) to (2B) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (2A) in THF at room temperature is treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 10, the conversion of (1N) to (3A) can be accomplished by treating the former with an epoxidizing reagent in a solvent. Specific examples of epoxidizing reagents include peracids, dioxirane, hydrogen peroxide and bases such as NaOH, KOH, and LiOH, and VO(acac)2 and tertiary-butylperoxide. More preferred are the following peracids: MCPBA, peracetic acid, and trifluoroperacetic acid. Specific examples of solvents include DCM, chloroform, cyclohexane, and hexanes.
Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (1N) in room temperature DCM is treated with MCPBA for about 16 hours.
The conversion of (3A) to (3B) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (3A) in THF at room temperature is treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 11, the conversion of (2A) to (4A) can be accomplished by treating the former with an epoxidizing reagent in a solvent. Specific examples of epoxidizing reagents include peracids, dioxirane, hydrogen peroxide and bases such as NaOH, KOH, and LiOH, and VO(acac)2 and tertiary-butylperoxide. More preferred are the following peracids: MCPBA, peracetic acid, and trifluoroperacetic acid. Specific examples of solvents include DCM, chloroform, cyclohexane, and hexanes. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (2A) in room temperature DCM is treated with MCPBA for about 16 hours.
The conversion of (4A) to (4B) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (4A) in THF at room temperature is treated with aqueous LIOH for about 10 hours. 
As shown in Scheme 12, the conversion of (2A) to (5A) can be accomplished by treating the former with an oxidant and bulk oxidant in a solvent. Specific examples of oxidant and bulk oxidants include the following: OsO4 and NMO, and KMnO4 with a base such as LiOH, NaOH, and KOH. Specific examples of solvents include toluene, benzene, xylene, acetone, tertiary-butyl alcohol, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (2A) in room temperature acetone is treated with water, NMO and OsO4 in toluene for about 3 hours. 
As shown in Scheme 13, the conversion of (4A) to (6A) an be accomplished by treating the former with a ucleophile and an additive in a solvent. Specific examples of nucleophiles include NaN3, TMSN3, TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN3, and TMSN3. Specific examples of additives include acids and bases. More preferred are the following acids: NH4Cl, (NH4)2SO4, and AcOH. Specific examples of solvents include MeOH, EtOH, i-PrOH, NMP, water, and mixtures thereof. Although the reaction generally proceeds at reflux, it can be run at lower temperatures as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (6A) in a methanol-water mixture is treated with NaN3 and NH4Cl and refluxed for about 5 hours.
The conversion of (6A) to (6B) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (6A) in THF at room temperature is treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 14, the conversion of (5A) to (7A) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include NaIO4, HIO4, and Pb(OAc)4. Specific examples of solvents include THF, methanol, ethanol, isopropanol, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (5A) in methanol at room temperature is treated with NaIO4 in water for about three hours.
The conversion of (7A) to (7B) can be accomplished by treating the former with an oxidizing agent and an additive in a solvent. Specific examples of oxidizing agents include sodium chlorite in acidic buffer, KMnO4, H2CrO4, AgO and Na2Cr2O7. A specific example of an additive is 2-methyl-2-butene. Specific examples of solvents include THF, DCM, tertiary-butyl alcohol, methanol, ethanol, and isopropanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (7A) in tertiary-butyl alcohol at room temperature is treated with sodium chlorite in KH2PO4 buffer and 2-methyl-2-butene for about 16 hours. 
As shown in Scheme 15, the conversion of (7A) to (8A) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (6A) in THF at room temperature is treated with aqueous LiOH for about 12 hours. 
As shown in Scheme 16, the conversion of (1N) to (9A) can be accomplished by treating the former with an oxidant in a solvent. Specific examples of oxidants include: OsO4 and NMO and KMnO4 and a base such as KOH, LiOH, and NaOH. Specific examples of solvents include toluene, benzene, xylene, acetone, and water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1N) in room temperature acetone is treated with water, NMO and OsO4 in toluene for about 3 hours.
The conversion of (9A) to (9B) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include NaIO4, HIO4, and Pb(OAc)4. Specific examples of solvents include THF, methanol, ethanol, isopropanol, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (5A) in methanol at room temperature is treated with NaIO4 in water for about three hours.
In an alternative synthesis, (9B) can be directly prepared from (1N) by treating the latter with a combination of oxidants in a solvent. Specific examples of oxidants include OsO4, and KMnO4 and a base such as KOH, LiOH, and NaOH, NaIO4, HIO4, and Pb(OAc)4. Specific examples of solvents include toluene, benzene, xylene, acetone, water, and mixture thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1N) in room temperature acetone is treated with water, OsO4, and NaIO4 for about three hours. 
As shown in Scheme 17, the conversion of (9B) to (9C) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include NaBH4, NaBH3CN, and BH3.NH2(C(CH3)3). Specific examples of solvents include methanol, ethanol, and isopropanol. Although the reaction generally proceeds at 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (9B) in methanol at 0xc2x0 C. is treated with NaBH4 for about 30 minutes.
The conversion of (9C) to (9D) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (9C) in THF at room temperature is treated with aqueous LiOH for about 12 hours. 
As shown in Scheme 18, the conversion of (1O) to (10A) can be accomplished by treating the former with a protecting group precursor, a base, and an additive in a solvent. A specific example of a protecting group precursor is 2-(trimethylsilyl)ethanol. A specific example of an additive is 2-chloro-1-methylpyridinium iodide. Specific examples of bases include TEA, diisopropylamine, and lutidine. Specific examples of solvents include DCM, THF, chloroform, and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1O) in room temperature DCM is treated with 2-(trimethylsilyl)ethanol, TEA and 2-chloro-1-methylpyridinium iodide for about 16 hours.
The conversion of (10A) to (10B) can be accomplished by treating the former with an oxidant and bulk oxidant in a solvent. Specific examples of oxidant and bulk oxidants include: OsO4 and NMO, and KMnO4 and a base such as KOH, LiOH, and NaOH. Specific examples of solvents include toluene, benzene, xylene, acetone, and water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (10A) in room temperature acetone is treated with water, OsO4 and NMO in toluene for about 3 hours. 
As shown in Scheme 19, the conversion of (10B) to (10C) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include NaIO4, HIO4, and Pb(OAc)4. Specific examples of solvents include THF, methanol, ethanol, isopropanol, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (10B) in methanol at room temperature is treated with NaIO4 in water for about three hours.
The conversion of (10C) to (10D) can be accomplished by treating the former with an oxidizing agent and an additive in a solvent to generate the acid which can then be esterified. Specific examples of oxidizing agents include sodium chlorite in acidic buffer, KMnO4, H2CrO4, AgO and Na2Cr2O7. A specific example of an additive is 2-methyl-2-butene. Specific examples of solvents include THF, DCM, tertiary-butyl alcohol, methanol, ethanol, and isopropanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (10C) in tertiary-butyl alcohol at room temperature is treated with sodium chlorite in KH2PO4 buffer and 2-methyl-2-butene for about 16 hours.
The acid can then be converted to (10D) by treating it with an esterifying reagent in a solvent. Specific examples of esterifying reagents include diazomethane, an alcohol and a mineral acid, and SOCl2 followed by an alcohol. Specific examples of solvents include methanol, THF, DCM, TBME, and chloroform. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 6 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (10D) in THF at 0xc2x0 C. is treated with diazomethane for about 30 minutes. 
As shown in Scheme 20, the conversion of (10D) to (10E) can be accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include TBAF, and HF. Specific examples of solvents include THF, DCM, chloroform, and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (10D) in THF at room temperature is treated TBAF for about three hours. 
As shown in Scheme 21, the conversion of (1B) to (11A) can be accomplished by treating the former with an organostannane and a free radical initiator in a solvent. Specific examples of organostannanes include 2-(tributylstannyl)furan, tributyltin hydride, allyltributyltin, vinyltributyltin, and 2-(tributylstannyl)thiophene. Specific examples of free radical initiators include AIBN, and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat. Specific examples of solvents include benzene, toluene, and xylene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1B), 2-methylallyl tributyltin and AIBN in benzene are refluxed for about 10 hours.
The conversion of (11A) to (11B) can be accomplished by treating the former with a catalyst and hydrogen, in a solvent. Specific examples of catalysts include palladium hydroxide, palladium on carbon, PdCl2, and platinum on carbon. Specific sources of hydrogen include ammonium formate and hydrogen gas. Specific examples of solvents include EtOAc, isopropyl acetate, and THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11A) in ethyl acetate at room temperature is treated with palladium hydroxide and 40 PSI of hydrogen for about 10 hours.
Example 22 
As shown in Scheme 22, the conversion of (11B) to (11C) can be accomplished by treating the former with sulfonyl chloride and a base in a solvent to generate an intermediate compound which can then be transesterified. Specific examples of sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride. Specific examples of bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11B) in DCM at 0xc2x0 C. is treated with methanesulfonyl chloride and TEA for about 5 hours.
The intermediate compound is then converted to (11C) by treating the former with a base and an alcohol. Specific examples of bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol and isopropanol. Co-solvents such as THF, TBME, DCM and chloroform can be added to the reaction mixture to enhance solubility of the starting materials and products. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the intermediate compound in methanol at room temperature is treated with potassium carbonate for about one hour.
The conversion of (11C) to (11D) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11C) in DCM at 0xc2x0 C. is treated with benzoyl chloride, and pyridine for about 5 hours. 
As shown in Scheme 23, the conversion of (11D) to (11E) can be accomplished by treating the former with sulfonyl chloride and a base in a solvent to generate an intermediate compound which can then be transesterified. Specific examples of sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride. Specific examples of bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11D) in DCM at 0xc2x0 C. is treated with methanesulfonyl chloride and TEA for about 10 hours.
The intermediate compound is then converted to (11E) by treating the former with a base and an alcohol. Specific examples of bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol and isopropanol. Co-solvents such as THF, TBME, DCM and chloroform can be added to the reaction mixture to enhance solubility of the starting materials and products. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the intermediate compound in methanol is treated with potassium carbonate for about 10 hours.
The conversion of (11E) to (11F) can be accomplished by treating the former with a base to generate an intermediate which is then treated with a nucleophile. Specific examples of bases include DBU, potassium tertiary-butoxide, and diisopropylethylamine. Specific examples of solvents include THF, chloroform, TBME, and benzene. Although the reaction generally proceeds at reflux, it can be run at lower temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11E) in THF is treated with DBU and refluxed for about 6 hours to generate an intermediate compound.
The conversion of the intermediate compound to (11F) can be accomplished by treating the former with a nucleophile and an additive. Specific examples of nucleophiles include NaN3, TMSN3, TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN3 and TMSN3. Specific examples of additives include acids and bases. More preferred are the following acids: NH4Cl, (NH4)2SO4, and AcOH. Specific examples of solvents include MeOH, EtOH, i-PrOH, NMP, water, and mixtures thereof. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, the intermediate compound in a methanol-water mixture is treated with NaN3 and NH4Cl and refluxed for about 5 hours.
Example 24 
As shown in Scheme 24, the conversion of (11F) to (11G) can be accomplished by treating the former with sulfonyl chloride and a base to generate an intermediate compound which can then be reduced to generate a second intermediate, protected to generate a third intermediate, treated with a Lewis acid and an alcohol to generate a fourth intermediate and acylated to generate 11H. Specific examples of sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride. Specific examples of bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11F) in DCM at 0xc2x0 C. is treated with methanesulfonyl chloride and TEA for about two hours to generate the first intermediate.
The conversion of the first intermediate to a second intermediate can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include phosphines followed by water and a base, and H2S and pyridine. More preferred are the following phosphines: PPh3, and PEt3. Specific examples of bases include TEA, NH4OH, and NaOH. Specific examples of solvents include THF, MeOH, TBME and DCM. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1K) in THF at room temperature is treated with PPh3 for about two hours, followed by water and TEA for about 10 hours.
The conversion of the second intermediate to the third intermediate can be accomplished by treating the former with a protecting group and a base in a solvent. Specific examples of protecting groups include trityl, nosyl and brosyl. Specific examples of base include pyridine, TEA and 2,6-lutidine. Specific examples of solvents include DCM, THF, chloroform and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the second intermediate in DCM at about 0xc2x0 C. is treated with trityl chloride and TEA for about two hours.
The conversion of the third intermediate to the fourth intermediate can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol. Specific examples of solvents include an aforementioned alcohol, THF, 1,1,1-trichloroethane, DCM and chloroform. Although the reaction generally proceeds at about 75xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the third intermediate in about 75xc2x0 C. isopropanol is treated with BF3.OEt2 for about two hours.
The conversion of the fourth intermediate to (11G) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the fourth intermediate in pyridine at room temperature is treated with acetic anhydride and pyridine for about 12 hours.
The conversion of (11G) to (11H) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (11G) in THF at room temperature is treated with aqueous LiOH for about 12 hours. 
As shown in Scheme 25, the conversion of (9C) to (12A) can be accomplished by treating the former with a phosphine, and a selenium compound in a solvent. Specific examples of phosphines include triphenylphosphine and tributylphosphine. A specific example of a selenium compound is ortho-nitrophenyl selenocyanate. Specific examples of solvents include THF, DCM, chloroform, and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (9C) in THF at room temperature is treated with tributylphosphine and ortho-nitrophenyl selenocyanate for about two hours.
The conversion of (12A) to (12B) can be accomplished by treating the former with a peroxide in a solvent. Specific examples of peroxides include hydrogen peroxide, di-tertiary-butyl peroxide, and ozone. Specific examples of solvents includes THF, DCM, chloroform, and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (12A) in THF at room temperature is treated with hydrogen peroxide for about 12 hours. 
As shown in Scheme 26, the conversion of (12B) to (12C) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (12B) in THF at room temperature is treated with aqueous LiOH for about 12 hours. 
As shown in Scheme 27, conversion of (i) to (13A) can be accomplished by treating the former with an aldehyde, ketone or acetal in the presence of an acid. Specific examples of aldehydes, ketones, and acetals include benzaldehyde, 4-methoxybenzaldehyde, acetaldehyde, 3-pentanone, and 2,2-dimethoxy propane. Specific examples of acids include para-toluenesulfonic acid, trifluoroacetic acid, and concentrated hydrochloric acid. Specific examples of solvents include benzene, toluene, xylene, dichloromethane, acetone, and mixtures thereof. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a solution of (i) in acetone is treated with 2,2-dimethoxy propane and para-toluenesulfonic acid and refluxed for about four hours.
The conversion of (13A) to (13B) can be achieved by treating the former with a base and an alcohol. Specific examples of bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol, and isopropanol. Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials and products. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13A) in methanol at room temperature is treated with potassium carbonate for about one hour.
The conversion of (13B) to (13C) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13B) in DCM at 0xc2x0 C. is treated with benzoyl chloride, and pyridine for about 12 hours.
The conversion of (13C) to (13D) can be accomplished by treating the former with a chloride source and a base in a solvent. Specific examples of chloride sources include thionyl chloride and sulfuryl chloride. Specific examples of bases include pyridine, DBU, diisopropylethylamine, and TEA. Specific examples of solvents include DCM, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13C) in DCM at 0xc2x0 C. is treated with sulfuryl chloride and pyridine for about three hours.
The conversion of (13D) to (13E) can be accomplished by treating the former with an acid in an alcohol. Specific examples of acids include para-toluenesulfonic acid, trifluoroacetic acid, and concentrated hydrochloric acid. Specific examples of alcohols include methanol, ethanol, and isopropanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13D) in methanol at room temperature is treated with para-toluenesulfonic acid for about 16 hours.
The conversion of (13E) to (13F) can be accomplished by treating the former with an activating group and a base in a solvent. A specific example of an activating group is thionyl chloride. Specific examples of bases include TEA, diisopropylethylamine pyrrolidine, and pyridine. Specific examples of solvents include THF, DCM, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13E) in DCM at 0xc2x0 C. is treated with thionyl chloride and TEA for about 30 minutes.
The conversion of (13F) to (13G) can be accomplished by treating the former with a nucleophile in a solvent. Specific examples of nucleophiles include NaN3, TMSN3, TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN3 and TMSN3. Specific examples of solvents include MeOH, EtOH, i-PrOH, DMF, NMP, water, and mixtures thereof. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure, it can be run at lower temperatures as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (13F) in room temperature DMF is treated with NaN3 for about 16 hours. 
As shown in Scheme 28, the conversion of (13G) to (13H) can be accomplished by treating the former with sulfonyl chloride and a base in a solvent. Specific examples of sulfonyl chlorides include methanesulfonyl chloride, para-toluenesulfonyl chloride, and trifluoromethanesulfonyl chloride. Specific examples of bases include TEA, pyridine, pyrrolidine, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13G) in DCM at 0xc2x0 C. is treated with methanesulfonyl chloride and TEA for about two hours.
The conversion of (13H) to (13I) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include phosphines followed by water and a base, and H2S and pyridine. More preferred are the following phosphines: PPh3, and PEt3. Specific examples of bases include TEA, NH4OH, and NaOH. Specific examples of solvents include THF, MeOH, TBME, and DCM. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13H) in THF at room temperature is treated with PPh3 for about two hours, followed by water and TEA for about 10 hours.
The conversion (13I) to (13J) can be accomplished by treating the former with a protecting group and a base in a solvent. Specific examples of protecting groups include trityl, nosyl, and brosyl. Specific examples of base include pyridine, TEA, and 2,6-lutidine. Specific examples of solvents include DCM, THF, chloroform, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13I) in DCM at about 0xc2x0 C. is treated with trityl chloride and TEA for about two hours.
The conversion of (13J) to (13K) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol. Specific examples of solvents include an aforementioned alcohol, THF, 1,1,1-trichloroethane, DCM, and chloroform. Although the reaction generally proceeds at about 75xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13J) in isopropanol is treated with BF3.OEt2 and heated to about 75xc2x0 C. for about two hours.
The conversion of (13K) to (13L) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13K)in pyridine is treated with acetic anhydride for about 12 hours.
The conversion of (13L) to (13M) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (13L) in THF at room temperature is treated with aqueous LiOH for about 12 hours. 
As shown in Scheme 29, the conversion of (13L) to (14A) can be accomplished by treating the former with a base and an alkylating agent in a solvent. Specific examples of alkylating agents include MeI, EtBr, allyl bromide, benzyl bromide, and isopropyl bromide. Specific examples of bases include NaH, KH, K2CO3, pyridine, and DBU. Specific examples of solvents include THF, DMF, DCM, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13L) in THF at 0xc2x0 C. is treated with NaH and allyl bromide for about 5 hours.
The conversion of (14A) to (14B) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (14A) in THF at room temperature is treated with aqueous LiOH for about 12 hours. 
As shown in Scheme 30, the conversion of (13L) to (15A) is accomplished by treating the former with a protecting group precursor and an additive in a solvent. Specific examples of protecting groups include vinyl ether, benzyl, TBS, and acetyl. Specific examples of additives include acids and bases. More preferred are the following acids: para-toluenesulfonic acid, triflic acid, TFA, and concentrated hydrochloric acid. Specific examples of solvents include vinyl ether, DCM, THF, and TBME. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13L) in room temperature vinyl ether is treated with TFA for about 16 hours.
The conversion of (15A) to (15B) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (15A) in THF at room temperature is treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 31, the conversion of (13L) to (16A) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include PCC coated on Al2O3, oxalyl chloride and DMSO, KMNO4, and Cr2O72xe2x88x92. Specific examples of solvents include DCM, THF, TBME, and diethyl ether.
Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a solution of (13L) in DCM can be treated with PCC on Al2O3 for about 8 hours.
The conversion of (16A) to (16B) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF, and TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates, and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, 1-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2-butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl)tributylstannane, vinyl magnesium bromide, and methyl magnesium bromide. Although the reaction generally proceeds at xe2x88x9278xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of vinyl magnesium bromide in THF can be treated with (16A) in THF for about two hours.
The conversion of (16B) to (16C) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (16B) in THF at room temperature can be treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 32, the conversion of (13B) to (17A) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13B) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about 10 hours.
The conversion of (17A) to (17B) is accomplished by treating the former with an acid in an alcohol. Specific examples of acids include para-toluenesulfonic acid, triflic acid, trifluoroacetic acid, and concentrated hydrochloric acid. Specific examples of alcohols include methanol, ethanol, and isopropanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17A) in methanol is treated with para-toluenesulfonic acid for about 16 hours.
The conversion of (17B) to (17C) is accomplished by treating the former with a base and an alcohol. Specific examples of bases include K2CO3, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol, and isopropanol. Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17B) in methanol at room temperature is treated with potassium carbonate for about 5 hours.
The conversion of (17C) to (17D) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17C) in DCM at about 0xc2x0 C. is treated with benzoyl chloride and TEA for about 5 hours.
The conversion of (17D) to (17E) can be accomplished by treating the former with a Lewis acid, a nucleophile, and a transition metal halide. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates, and nitriles. More preferred are the following Grignard reagents: vinyl magnesium bromide, methylmagnesium bromide, and ethylmagnesium bromide. Specific examples of transition metal halides include CuI, and CuBr. Specific examples of solvents include THF, diethyl ether, and TBME. Although the reaction generally proceeds at about xe2x88x9278xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a suspension of CuI and vinyl magnesium bromide in xe2x88x9278xc2x0 C. THF can be treated with a solution of (17D) and BF3.OEt2 in THF. 
As shown in Scheme 33, the conversion of (17E) to (17F) is accomplished by treating the former with a base and an alcohol. Specific examples of bases include K2CO3, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol, and isopropanol. Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17E) in methanol at room temperature can be treated with potassium carbonate for about one hour.
The conversion of (17F) to (17G) can be accomplished by treating the former with an activating group and a base in a solvent. A specific example of an activating group is thionyl chloride. Specific examples of bases include TEA, diisopropylethylamine pyrrolidine, and pyridine. Specific examples of solvents include THF, DCM, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17F) in DCM at 0xc2x0 C. can be treated with thionyl chloride and TEA for about 30 minutes.
The conversion of (17G) to (17H) can be accomplished by treating the former with a nucleophile in a solvent. Specific examples of nucleophiles include NaN3, TMSN3, TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN3 and TMSN3. Specific examples of solvents include MeOH, EtOH, i-PrOH, NMP, DMF, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (17G) in room temperature DMF can be treated with NaN3 for about 16 hours.
The conversion of (17H) to (17I) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17H) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about two hours.
The conversion of (17I) to (17J) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include phosphines followed by water and a base, and H2S and pyridine. More preferred are the following phosphines: PPh3, and PEt3. Specific examples of bases include TEA, NH4OH, and NaOH. Specific examples of solvents include THF, MeOH, TBME, and DCM. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17I) in THF at room temperature can be treated with PPh3 for about two hours, followed by water and TEA for about 10 hours. 
As shown in Scheme 34, the conversion of (17J) to (17K) can be accomplished by treating the former with a protecting group and a base in a solvent. Specific examples of protecting groups include trityl, nosyl, and brosyl. Specific examples of base include pyridine, TEA, and 2,6-lutidine. Specific examples of solvents include DCM, THF, chloroform, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17J) in DCM at about 0xc2x0 C. can be treated with trityl chloride and TEA for about two hours.
The conversion of (17K) to (17L) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol. Specific examples of solvents include an aforementioned alcohol, THF, 1,1,1-trichloroethane, DCM, and chloroform. Although the reaction generally proceeds at about 75xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17K) in isopropanol can be treated with BF3.OEt2 and heated to about 75xc2x0 C. for about two hours.
The conversion of the intermediate to (17L) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the intermediate in pyridine at room temperature can be treated with acetic anhydride and pyridine for about 12 hours.
The conversion of (17L) to (17M) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (17L) in THF at room temperature can be treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 35, the conversion of (1A) to (18A) can be accomplished by treating the former with a base and an alcohol. Specific examples of bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol, and isopropanol. Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (lA) in methanol at room temperature can be treated with potassium carbonate for about one hour.
The conversion of (18A) to (18B) can be accomplished by treating the former with a protecting group precursor and an additive in a solvent. Specific examples of protecting groups include benzyl, TMS, TES, and TBDMS. Specific examples of additives include acids and bases. More preferred are the following bases: pyridine, TEA, DMAP, imidazole, and 2,6-lutidine. Specific examples of solvents include DCM, THF, chloroform, DMF, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18A) in DMF at 0xc2x0 C. can be treated with TBDMSCl and imidazole for about 16 hours.
The conversion of (18B) to (18C) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18B) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about 16 hours.
Conversion of (18C) to (18D) can be accomplished by treating the former with a free radical precursor and a free radical initiator in a solvent. Specific examples of free radical precursors include N-bromosuccinimide, N-chlorosuccinimide, Br2, and Cl2. Specific examples of free radical initiators include AIBN, and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat. Specific examples of solvents include benzene, toluene, and xylene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18C) can be treated with AIBN and N-bromosuccinimide in refluxing benzene for about four hours.
The conversion of (18D) to (18E) can be accomplished by treating the former with an organostannane and a free radical initiator in a solvent. Specific examples of organostannanes include 2-(tributylstannyl)furan, tributyltin hydride, allyltributyltin, vinyltributyltin, and 2-(tributylstannyl)thiophene. Specific examples of free radical initiators include AIBN, and di-tertiary-butyl peroxide in the presence of ultraviolet light or heat. Specific examples of solvents include benzene, toluene, and xylene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18D), allyltributyltin and AIBN in benzene can be refluxed for about 10 hours. 
As shown in Scheme 36, the conversion of (18E) to (18F) can be accomplished by first, treating the former with a base and an alcohol to form the first intermediate, which can then be treated with a sulfonyl chloride and base to yield the second intermediate, which can be treated with a deprotecting agent to yield (18F). Specific examples of bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol, and isopropanol. Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18E) in methanol at room temperature can be treated with potassium carbonate for about 16 hours.
The conversion of the first intermediate to the second intermediate can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the first intermediate in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride, and TEA for about 12 hours.
The conversion of the third intermediate to (18F) can be accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include HF and TBAF. Specific examples of solvents include THF, DCM, TBME, and diethylether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the third intermediate in THF at room temperature can be treated with TBAF for about 12 hours.
The conversion of (18F) to (18G) can be accomplished by treating the former with a nucleophile in a solvent. Specific examples of nucleophiles include NaN3, TMSN3, TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN3 and TMSN3. Specific examples of solvents include MeOH, EtOH, i-PrOH, NMP, DMF, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (18F) in room temperature DMF can be treated with NaN3 for about 16 hours.
The conversion of (18G) to (18H) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18G) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about two hours.
The conversion of (18H) to (18I) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include phosphines followed by water and a base, and H2S and pyridine. More preferred are the following phosphines: PPh3, and PEt3. Specific examples of bases include TEA, NH4OH, and NaOH. Specific examples of solvents include THF, MeOH, TBME, and DCM. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18H) in THF at room temperature can be treated with PPh3 for about two hours, followed by water and TEA for about 10 hours.
The conversion of (18I) to (18J) can be accomplished by treating the former with a protecting group and a base in a solvent. Specific examples of protecting groups include trityl, nosyl, and brosyl. Specific examples of base include pyridine, TEA, and 2,6-lutidine. Specific examples of solvents include DCM, THF, chloroform, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18I) in DCM at about 0xc2x0 C. can be treated with trityl chloride and TEA for about two hours.
The conversion of (18J) to (18K) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol. Specific examples of solvents include an aforementioned alcohol, THF, 1,1,1-trichloroethane, DCM, and chloroform. Although the reaction generally proceeds at about 75xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18J) in isopropanol can be treated with BF3.OEt2 and heated to about 75xc2x0 C. for about two hours.
The conversion of the intermediate to (18K) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the intermediate in pyridine at room temperature can be treated with acetic anhydride and pyridine for about 12 hours.
The conversion of (18K) to (18L) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (18K) in THF at room temperature can be treated with aqueous LiOH for about 10 hours. 
As shown in Scheme 37, the conversion of (18D) to (19A) can be accomplished by treating the former with a transition metal catalyst and an organostannane in a solvent. Specific examples of a transition metal catalysts include palladium on carbon, platinum on carbon, PdCl2, Pd(PPh3)4, and bis(dibenzylidenacetone)palladium(O). It can be necessary to add a ligand for the transition metal catalyst. Specific examples include triphenylphosphine, dba, and dppf. Specific examples of organostannanes include vinyltributyltin, (ethoxyethyloxymethyl)tributylstannane, and allyltributyltin. Specific examples of solvents include THF, TBME,, and diethylether. Although the reaction generally proceeds at about 55xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 24 hours to about 48 hours and can be selected depending on the types of starting materials and the reaction temperature. In a preferred embodiment, (18D) in THF can be treated with triphenylphosphine, vinyltributyltin, and bis(dibenzylideneacetone)palladium(0) and heated to about 55xc2x0 C. for about 24 hours. 
As shown in Scheme 38, the conversion of (19A) to (19B) can be accomplished by first, treating the former with a base and an alcohol to form the first intermediate, which can then be treated with a sulfonyl chloride and base to yield the second intermediate, which can be treated with a deprotecting agent to yield (19B). Specific examples of bases include potassium carbonate, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include methanol, ethanol, propanol, and isopropanol. Co-solvents such as THF, TBME, DCM, and chloroform can be added to the reaction mixture to enhance solubility of the starting materials. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19A) in methanol at room temperature can be treated with potassium carbonate for about 16 hours.
The conversion of the first intermediate to the second intermediate can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the first intermediate in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about 12 hours.
The conversion of the third intermediate to (19B) can be accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include HF and TBAF. Specific examples of solvents include THF, DCM, TBME, and diethylether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 18 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the third intermediate in THF at room temperature can be treated with TBAF for about 12 hours.
The conversion of (19B) to (19C) can be accomplished by treating the former with a nucleophile in a solvent. Specific examples of nucleophiles include NaN3, TMSN3, TMSCl, TMSBr, carbanions, thioacetate, and cyanide. More preferred are the following nucleophiles: NaN3 and TMSN3. Specific examples of solvents include MeOH, EtOH, i-PrOH, NMP, DMF, water, and mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (19B) in room temperature DMF can be treated with NaN3 for about 16 hours.
The conversion of (19C) to (19D) can be accomplished by treating the former with a hydroxyl activating group precursor and an additive in a solvent. Specific examples of hydroxyl activating group precursors include trifluoroacetic anhydride, azo compounds such as DEAD, DIAD, and AIBN and phosphines such as PPh3, and PBu3, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of additives include acids and bases. More preferred are the following bases: KOH, TEA, pyridine, pyrrolidine, DMAP, DBU, and diisopropylethylamine. Specific examples of solvents include DCM, chloroform, THF, TBME, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19C) in DCM at about 0xc2x0 C., is treated with methanesulfonyl chloride and TEA for about two hours.
The conversion of (19D) to (19E) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include phosphines followed by water and a base, and H2S and pyridine. More preferred are the following phosphines: PPh3, and PEt3. Specific examples of bases include TEA, NH4OH, and NaOH. Specific examples of solvents include THF, MeOH, TBME, and DCM. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19D) in THF at room temperature can be treated with PPh3 for about two hours, followed by water and TEA for about 10 hours.
The conversion of (19E) to (19F) can be accomplished by treating the former with a protecting group and a base in a solvent. Specific examples of protecting groups include trityl, nosyl, and brosyl. Specific examples of base include pyridine, TEA, and 2,6-lutidine. Specific examples of solvents include DCM, THF, chloroform, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19E in DCM at about 0xc2x0 C. can be treated with trityl chloride and TEA for about two hours.
The conversion of (19F) to (19G) can be accomplished by treating the former with a Lewis acid and an alcohol in a solvent to afford an intermediate which can then be treated with an acylating agent and a base. Specific examples of Lewis acids include ZnCl2, TiCl4, BF3.OEt2, and SnCl4. Specific examples of alcohols include methanol, ethanol, isopropanol, 3-pentanol, benzhydrol, and benzyl alcohol. Specific examples of solvents include an aforementioned alcohol, THF, 1,1,1-trichloroethane, DCM, and chloroform. Although the reaction generally proceeds at about 75xc2x0 C., it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19F) in isopropanol can be treated with BF3.OEt2 and heated to about 75xc2x0 C. for about two hours.
The conversion of the intermediate to (19G) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of bases include TEA, DMAP, pyrrolidine, diisopropylethylamine, and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine, and diethyl ether. Although the reaction generally proceeds at about 0xc2x0 C., it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the intermediate in pyridine at room temperature can be treated with acetic anhydride and pyridine for about 12 hours.
The conversion of (19G) to (19H) can be accomplished by treating the former with a hydrolyzing agent in a solvent. Specific examples of hydrolyzing agents include acids and bases. More preferred are the following bases: LiOH, KOH, and NaOH. Specific examples of solvents include THF, MeOH, DCM, diethyl ether, and chloroform. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (19G) in THF at room temperature can be treated with aqueous LiOH for about 10 hours.
Compounds of formula Ia and Ib include compounds of formula Iaxe2x80x2 and Iaxe2x80x2. Compounds of formula Ib include compounds of formula Ibxe2x80x2 and Ibxe2x80x3. Representative compounds of formulas Ia and Ib include:
(3R,4R,5S)-4-(acetylamino)-5-allyl-3-isopropoxy-1-cyclohexene-1-carboxylic acid;
(3R,4R,5S)-4-(acetylamino)-5-allyl-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-3-isopropoxy-5-(2-oxiranylmethyl)-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-3-(1-ethylpropoxy)-5-(2-oxiranylmethyl)-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-5-(2,3-dihydroxypropyl)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-5-(3-azido-2-hydroxypropyl)-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid;
[(1R,5R,6R)-6-(acetylamino)-5-(1-ethylpropoxy)-3-(methoxycarbonyl)-3-cyclohexen-1-yl]acetic acid;
(3R,4R,5R)-4-(acetylamino)-3-(1-ethylpropoxy)-5-(2-oxoethyl)-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-5-(2-hydroxyethyl)-3-isopropoxy-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-3-isopropoxy-5-(2-methoxy-2-oxoethyl)-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-3-isopropoxy-5-isopropyl-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-3-isopropoxy-5-vinyl-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-5-hydroxy-3-isopropoxy-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-5-(allyloxy)-3-isopropoxy-1-cyclohexene-1-carboxylic acid;
(3R,4R,5R)-4-(acetylamino)-5-(1-ethoxyethoxy)-3-isopropoxy-1-cyclohexene-1-carboxylic acid;
methyl (3R,4S,5S)-4-(acetylamino)-5-hydroxy-3-isopropoxy-5-vinyl-1-cyclohexene-1-carboxylate;
methyl (3R,4R,5S)-4-(acetylamino)-3-isopropoxy-5-vinyl-1-cyclohexene-1-carboxylate;
(3S,4R,5R)-4-(acetylamino)-3-allyl-5-isopropoxy-1-cyclohexene-1-carboxylic acid; and
(3S,4R,5R)-4-(acetylamino)-5-isopropoxy-3-vinyl-1-cyclohexene-1-carboxylic acid.
Preferred compounds of formula Ia and Ib are those in which R1 is xe2x80x94CO2H, X is xe2x80x94N(R*)xe2x80x94C(xe2x95x90O)xe2x80x94, R* is hydrogen, xe2x80x94R2 is C1-C6 alkyl, R15 is xe2x80x94Oalkyl, and Y is C2-C5 alkenyl.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, trifluoroacetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, lithium, calcium or magnesium or with ammonium or N(R**)4+ salts (where R** is loweralkyl).
In addition, salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.
Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate.
The compounds of the formula Ia or Ib of this invention can have a substituent which is an acid group (for example, xe2x80x94CO2H, xe2x80x94SO3H, xe2x80x94SO2H, xe2x80x94PO3H2, xe2x80x94PO2H). Compounds of the formula Ia or Ib of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention. Such esters may serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of formula Ia or Ib. Prodrugs may also serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract. These prodrugs may also serve to increase solubility for intravenous administration of the compounds. Prodrugs may also serve to increase the hydrophobicity of the compounds. Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism. Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues and/or reduced rate of clearance.
Such esters contemplated by this invention include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t-butoxymethyl esters and the like;
alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyl esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;
aryloxyalkyl esters, especially, aryloxy-substituted loweralkyl esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;
haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyl esters, including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the like;
alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substituted loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters and the like;
cyanoalkyl esters, especially, cyano-substituted loweralkyl esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;
thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like;
alkylsulfonylalkyl esters, especially, loweralkylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;
arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-benzenesulfonylethyl and 2-toluenesulfonylethyl esters and the like;
acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyl esters, including, but not limited to, formyloxymethyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl esters and the like;
cycloalkylcarbonyloxyalkyl esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxyethyl esters and the like;
arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyl esters and the like;
(alkoxycarbonyloxy)alkyl esters, especially, (loweralkoxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl esters and the like;
(cycloalkyloxycarbonyloxy)alkyl esters, especially, (cycloalkyloxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters and the like;
oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-tluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl esters and the like;
phthalidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl esters and the like;
aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like;
arylalkyl esters, especially, aryl-substitued loweralkyl esters, including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyl esters, including, but not limited to, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl ester and the like
(heterocyclic)alkyl esters, especially, heterocyclic-substituted loweralkyl esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic)methyl esters and the like, wherein the heterocyclic part of the (heterocyclic)alkyl group is unsubstituted or substituted as previously defined herein; and
carboxyalkyl esters, especially, carboxy-substituted loweralkyl esters, including, but not limited to carboxymethyl esters and the like;
and the like.
Preferred prodrug esters of acid-containing compounds of the Formula Ia or Ib are loweralkyl esters, including, but not limited to, ethyl, n-propyl,-isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters, 3-pentyl esters, cycloalkyl esters, cycloalkylalkyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.
Methods for the preparation of prodrug esters of compounds of the Formula Ia or Ib are well-known in the art and include:
reacting the acid with the corresponding halide (for example, chloride or acyl chloride) and a base (for example, triethylamine, DBU, N,N-dimethylaminopyridine and the like) in an inert solvent (for example, DMF, acetonitrile, N-methylpyrrolidone and the like);
reacting an activated derivative of the acid (for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like) with the corresponding alcohol or alkoxide salt; and the like.
Other examples of prodrugs of the present invention include amides derived from the substituent which is an acid group.
Such amides contemplated by this invention include:
simple amides, such as xe2x80x94C(O)NH2 and the like;
alkylamino amides, especially, loweralkylamino amides, including, but not limited to, methylamino, ethylamino, n-propylamino, isopropylamino amides and the like;
cylcoalkylamino amides, including, but not limited to, cylopropylamino, cylcobutylamino, cyclopentylamino, cyclohexylamino amides and the like;
acylamino amides, including, but not limited to acetylamino, propionylamino, butanoylamino amides and the like;
cylcoalkylcarbonylamino amides, including, but not limited to, cyclopropylcarbonylamino, cyclobutylcarbonylamino amides and the like;
alkoxycarbonylalkylamino amides, including, but not limited to, ethoxycarbonylmethylamino, t-butyloxycarbonylmethylamino and the like;
aminoacylamino amides, including, but not limited to, aminoacetylamino amides and the like;
dialkylaminoacylamino amides, including, but not limited to, dimethylaminoacetylamino, diethylaminoacetylamino amides and the like;
(heterocyclic)acylamino amides, including, but not limited to, piperidin-1-ylacetylamino amides and the like;
amides derived from single naturally occuring L-amino acids (or from acid-protected L-amino acids, for example, esters of such amino acids and the like) or from dipeptides comprising two naturally occuring L-amino acids wherein each of the two amino acids is the same or is different (or from acid-protected dipeptides, for example, esters of such dipeptides and the like);
and the like.
Methods for preparation of prodrug amides of compounds of the invention are well-known in the art and include reacting the acid with the appropriate amine in the presence of an amide bond or peptide bond-forming coupling reagent or reacting an activated derivative of the acid with the appropriate amine and the like.
Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of formula Ia and Ib which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R100C(O)xe2x80x94 or R100C(S)xe2x80x94 wherein R100 is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula Raxe2x80x94C(Rb)(Rd)xe2x80x94C(O)xe2x80x94 or Raxe2x80x94C(Rb)(Rd)xe2x80x94C(S)xe2x80x94 wherein Rb and Rd are independently selected from hydrogen or lower alkyl and Ra is xe2x80x94N(Re)(Rf), xe2x80x94ORe or xe2x80x94SRe wherein Re and Rf are independently selected from hydrogen, lower alkyl and haloalkyl, or an amino-acyl residue having the formula R101NH(CH2)2NHCH2C(O)xe2x80x94 or R101NH(CH2)2OCH2C(O)xe2x80x94 wherein R101 is hydrogen, lower alkyl, (aryl)alkyl, (cycloalkyl)alkyl, acyl, benzoyl or an -amino acyl group. The amino acid esters of particular interest are of glycine and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyl group is xe2x80x94C(O)CH2NR102R103 wherein R102 and R103 are independently selected from hydrogen and lower alkyl, or the group xe2x80x94NR102 R103, where R102 and R103, taken together, forms a nitrogen containing heterocyclic ring.
Other prodrugs include a hydroxyl-substituted compound of formula Ia and Ib wherein the hydroxyl group is functionalized with a substituent of the formula xe2x80x94CH(R104)OC(O)R105 or xe2x80x94CH(R104)OC(S)R105 wherein R105 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R104 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.
The preparation of esters of hydroxyl-substituted compounds of formula Ia and Ib is carried out by reacting a hydroxyl-substituted compound of formula formula Ia or Ib with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.
Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation of the hydroxyl substituted compound of formula formula Ia or Ib with (halo)alkyl esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
In preparing prodrugs it often is necessary to protect other reactive functional groups, in order to prevent unwanted side reactions. After protection of the reactive groups the desired group can be functionalized. The resulting functionalized product is then deprotected, to remove the protecting groups that were added to prevent unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. One source for reaction conditions is found in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991).
This invention also encompasses compounds of the Formula Ia or Ib which are esters or prodrugs and which are also salts. For example, a compound of the invention can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent in the same compound.
The compounds of the present invention are useful for inhibiting neuraminidase from disease-causing microorganisms which comprise a neuraminidase. The compounds of the invention are useful (in humans, other mammals and fowl) for treating or preventing diseases caused by microorganisms which comprise a neuraminidase.
The compounds of the present invention are useful for inhibiting influenza A virus neuraminidase and influenza B virus neuraminidase, in vitro or in vivo (especially in mammals and, in particular, in humans). The compounds of the present invention are also useful for the inhibition of influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the inhibition of influenza A viruses and influenza B viruses in humans and other mammals. The compounds of the present invention are also useful for the treatment of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the human diseases caused by influenza A and influenza B viruses.
The compounds of the present invention are also useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of influenza A and influenza B viral infections; and, in particular, the prophylaxis of influenza A and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.
Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms and/or the confirmation of infection.
The compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder (for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more anti-infective agents and/or other agents used to treat other acute or chronic respiratory ailments. Other agents to be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, clarithromycin, azithromycin and the like; and agents used to treat asthma, such as, for example, zileuton, albuterol (salbutamol), salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, cromolyn, zafirlukast, montelukast used in combination with a compound of the present invention. When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The ability of the compounds of the invention to inhibit neuraminidase in vitro can be determined according to the method described below.
Neuraminidase Inhibition Assay
Influenza virus A/N1/PR/8/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Laver, W. G. (1969) in xe2x80x9cFundamental Techniques in Virologyxe2x80x9d (K. Habel and N. P. Salzman, eds.) pp. 92-86, Academic Press, New York). Influenza virus A/N2/Tokyo/3/67 was obtained from the tissue culture supernatents of virus grown on MDCK cells. Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Laver, W. G., Luo, M., Stray, S. J., Legrone, G., and Webster, R. G. (1990) Virology 177, 578-587).
The neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/N1/PR/8/34 or A/N2/Tokyo/3/67 whole virus, or the B/Memphis/3/89 catalytic head fragment. The whole virus or catalytic fragment was diluted appropriately with 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO. Reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30 xcexcM 4-methylumbelliferyl sialic acid substrate in a total volume of 200 xcexcL and were contained in white 96-well U-shaped plates. Typically, five to eight concentrations of inhibitor were used for each Ki value measurement. The reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan II plate reader (ICN Biomedical) equipped with excitation and emission filters of 355+/xe2x88x9235 nm and 460+/xe2x88x9225 nm, respectively. The plate reader was under the control of DeltaSoft II software (Biometallics) and a Macintosh computer. If the compound exhibited linear reaction velocities during the reaction period, then the reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-Interscience, New York).
(1xe2x88x92Vi/Vo)=[I]/{[I]+Ki(1+[S]/Km)}xe2x80x83xe2x80x83eqn 1
In equation 1, Vi and Vo represent inhibited and uninhibited reaction velocities, respectively, and Km=16-40 xcexcM depending on the neuraminidase strain tested. For those compounds exhibiting slow-binding inhibition (Morrison, J. F. (1982) Trends Biochem. Sci. 7, 102-105), a second experiment was performed in a manner identical to the first except that neuraminidase and inhibitor were preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate. Data analysis for the resulting linear velocities was conducted as described above.
Equation 2 was used to measure Ki values in the sub-nanomolar range (Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2, 347-368).
V=A{sqrt{(Kixe2x80x2+Itxe2x88x92Et){circumflex over ( )}2+4Kixe2x80x2Et}xe2x88x92(Kixe2x80x2+Itxe2x88x92Et)]xe2x80x83xe2x80x83eqn. 2
In equation 2, V=velocity; A=xcex1kcat[S]/2(Km+[S]); xcex1 is a factor to convert fluorescence units to molar concentrations; Kixe2x80x2=Ki(1+[S]/Km); It=total inhibitor concentration and Et=total active concentration of neuraminidase.
The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 0.1 nanomolar and about 500 micromolar. Preferred compounds of the invention invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 0.1 nanomolar and about 3.5 micromolar.
The ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.
Cell Culture Plaque Formation Inhibition Assay
Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco""s Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mM HEPES buffer (GibcoBRL) and antibiotics (GibcoBRL). Cells were routinely cultured in flasks or roller bottles at 37xc2x0 C. and 5% CO2. At confluence cells were reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayer followed by cell centrifugation, resuspension, and dilution into growth media. Cells were planted at a volume to surface area ratio of 1 ml over 1 cm2 of growth surface.
Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1% fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza A/Tokyo/3/67 [H2N2]) (40-100 plaque forming units) and 2xc3x97 concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared. In a microwave oven 2xc3x97 agarose (final concentration of 0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted and then placed in a 48xc2x0 C. water bath for temperature equilibration. After the virus adsorption period was completed 1.5 ml agar over media was added and mixed with the 1.5 ml virus and test compound containing media per well.
Cultures were incubated at 35xc2x0 C. for the period required for plaque development, usually several days. Plaques were fixed with 3.7% formalin in PBS for 20 minutes followed by removal of the agar overlay and staining with 0.1% crystal violet in distilled water for 15 minutes. Plaques were counted and EC 50 concentration determined from multiple concentrations of the tested compound using regression analysis.
Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated at 37xc2x0 C. in DMEM supplemented with 1% FCS, 40 mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell lysate. Stocks were titered and stored at xe2x88x9280xc2x0 C.
Compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 100 micromolar and about 1 nanomolar. Preferred compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 1 micromolar and about 1 nanomolar.
The compounds of the invention can be tested for in vivo antiviral activity using the method described below.
In Vivo Antiviral Efficacy Method
Female BALB/c mice were placed under anesthesia (sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8-34) at 10xe2x88x922 (diluted from frozen stock). This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4 h. pre-infection and 4 h. post-infection, and periodically thereafter, with one of the following therapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kg/day BID, PO); or vehicle (sterile water BID, PO). A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined. On day five, lungs were harvested, weighed and assigned scores of 0, 1, 2, 3 or 4 based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pair was image analyzed to determine objective lung consolidation percentages.